Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia.
Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events.
Kearney
Lyndal
L
Section of Haemato-Oncology, The Institute of Cancer Research, Sutton, United Kingdom. lyndal.kearney@icr.ac.uk
Gonzalez De Castro
David
D
Yeung
Jenny
J
Procter
Julia
J
Horsley
Sharon W
SW
Eguchi-Ishimae
Minenori
M
Bateman
Caroline M
CM
Anderson
Kristina
K
Chaplin
Tracy
T
Young
Bryan D
BD
Harrison
Christine J
CJ
Kempski
Helena
H
So
Chi Wai E
CW
Ford
Anthony M
AM
Greaves
Mel
M
D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D009154:Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
D053614:Janus Kinase 2